Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells.

Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects. AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE −/− mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro. α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro , as well as in vivo using the air pouch model. Treating apoE −/− mice with AZ6983 decreased atherosclerosis by 37–49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages. This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE −/− mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans. Image 1 • The novel selective α7nAChR agonist AZ6983 decreases atherosclerosis in mice via immunomodulating effects. • α7nAChR agonist AZ6983 enhances phagocytosis of apoptotic macrophages in vitro. • α7nAChR agonist AZ6983 provides local anti-inflammatory effects in atherosclerotic lesions and in acute inflammatory models. • α7nAChR agonist AZ6983 decreases inflammatory cytokines in human blood in vitro , and systemically in vivo. • α7nAChR agonist AZ6983 can be an attractive therapeutic target for preventing atherosclerosis. [ABSTRACT FROM AUTHOR]